Metastatic melanoma is a deadly disease with an expected five-year survival of only 14%. The goal of this project is to better understand the environmental and genetic factors which cause this often-fatal disease in the hope that we may suggest approaches for disease prevention and therapeutic intervention Epidemiology has suggested that ultraviolet (UV) radiation and the red/blond, fair-skinned pigmentation phenotype are two major melanoma risk factors. However, genetically controlled experiments to establish an unambiguous causative link is lacking. This project aims to create a series of mouse models for two main objectives: (1) to establish a clear link between UV, pigmentation and melanoma in order to provide better public health information, and (2) to use these mouse models to understand the molecular mechanisms by which UV and high risk pigmentation variants produce melanoma. In order to produce a novel melanoma mouse model, red/blond, albino, and black mice which also carry an activatable form of BRAF or NRAS (the most commonly mutated oncogenes in melanoma) are being generated. Preliminary experiments using this system have already revealed the striking observation that a significant number of the red/blond mice develop melanomas, while none of the albino mice and very few of the black mice develop the same lesions. With this data suggesting there is a strong genetic tumorogenic effect of the red/blond phenotype, it is likely that examining the role of UV will provide exciting new information. To pursue the first aim, melanoma rates between UV irradiated red/blond, albino, and black mice will be compared to determine the effects of pigmentation and UV alone. Next, melanoma rates between UV irradiated black mice that carry either of the 2 most commonly mutated oncogenes in melanoma (BRAF or NRAS) will be compared to determine the effects of oncogene activation and UV irradiation. Lastly, melanoma rates after UV irradiation of red/blond and albino mice carrying the same mutated oncogenes will be compared to see how the 3 variables work together to alter melanoma risk. The goal of the second aim is to understand the mechanisms by which UV and the red/blond phenotpye induce disease. Initially it will be investigated if the high rate of melanoma in the red/blond context is pigmentation dependent. Next, it will be investigated if the mechanism of red/blond-melanoma is via reactive oxidative damage, as suggested by previous studies showing that red/blond pigment can promote release of reactive oxidative species (ROS). To investigate this question, the types of DNA damage in UV irradiated red/blond, albino, and black mice will be compared. Finally, the ROS burden in melanocytes will be genetically and pharmacologically altered to investigate if this strategy can block red/blond-melanoma induction.